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Improved Reperfusion and Vasculoprotection by the Poly(ADP-Ribose)Polymerase Inhibitor PJ34 After Stroke and Thrombolysis in Mice

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Abstract

Benefits from thrombolysis with recombinant tissue plasminogen activator (rt-PA) after ischemic stroke remain limited due to a narrow therapeutic window, low reperfusion rates, and increased risk of hemorrhagic transformations (HT). Experimental data showed that rt-PA enhances the post-ischemic activation of poly(ADP-ribose)polymerase (PARP) which in turn contributes to blood-brain barrier injury. The aim of the present study was to evaluate whether PJ34, a potent PARP inhibitor, improves poor reperfusion induced by delayed rt-PA administration, exerts vasculoprotective effects, and finally increases the therapeutic window of rt-PA. Stroke was induced by thrombin injection (0.75 UI in 1 μl) in the left middle cerebral artery (MCA) of male Swiss mice. Administration of rt-PA (0.9 mg kg−1) or saline was delayed for 4 h after ischemia onset. Saline or PJ34 (3 mg kg−1) was given intraperitoneally twice, just after thrombin injection and 3 h later, or once, 3 h after ischemia onset. Reperfusion was evaluated by laser Doppler, vascular inflammation by immunohistochemistry of vascular cell adhesion molecule-1 (VCAM-1) expression, and vasospasm by morphometric measurement of the MCA. Edema, cortical lesion, and sensorimotor deficit were evaluated. Treatment with PJ34 improved rt-PA-induced reperfusion and promoted vascular protection including reduction in vascular inflammation (decrease in VCAM-1 expression), HT, and MCA vasospasm. Additionally, the combined treatment significantly reduced brain edema, cortical lesion, and sensorimotor deficit. In conclusion, the combination of the PARP inhibitor PJ34 with rt-PA after cerebral ischemia may be of particular interest in order to improve thrombolysis with an extended therapeutic window.

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Abbreviations

BBB:

Blood-brain barrier

CBF:

Cerebral blood flow

DAB:

3,3′-Diaminobenzidine tetrahydrochloride

MCA:

Middle cerebral artery

PARP:

Poly(ADP-ribose)polymerase

PJ34:

N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-(N,N-dimethylamino)acetamide hydrochloride

ROI:

Region of interest

rt-PA:

Recombinant tissue plasminogen activator

VCAM-1:

Vascular cell adhesion molecule-1

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Funding

M. El-Amki and. M. Garraud are recipients of a Ph.D. grant from the Université Paris Descartes, Université Sorbonne Paris Cité.

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Authors and Affiliations

  1. EA4475 - “Pharmacologie de la Circulation Cérébrale”, Faculté de Pharmacie de Paris, Université Paris Descartes, Université Sorbonne Paris Cité, 4 avenue de l’Observatoire, 75006, Paris, France

    Mohamad El Amki, Dominique Lerouet, Marie Garraud, Fei Teng, Virginie Beray-Berthat, Bérard Coqueran, Benoît Barsacq, Charlotte Abbou, Bruno Palmier, Catherine Marchand-Leroux & Isabelle Margaill

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  1. Mohamad El Amki
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Contributions

DL, MEA, and IM conceived and designed the experiments. MEA, MG, BB, and CA performed the experiments. MEA, DL, BP, and BC analyzed the data. MEA, DL, VBB, CML, and IM wrote the manuscript.

Corresponding author

Correspondence to Isabelle Margaill.

Ethics declarations

All experiments were performed on male Swiss albino mice (25–32 g, Janvier, Le Genest-St-Isle, France) in compliance with the European Community Council Directive of September 22, 2010 (2010/63/UE), and the French regulations regarding the protection of animals used for experimental and other scientific purposes (D2013-118), with the ethical approval of the Paris Descartes University Animal Ethics Committee (registered number P2.CM.152.10).

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The authors declare that they have no conflicts of interest.

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El Amki, M., Lerouet, D., Garraud, M. et al. Improved Reperfusion and Vasculoprotection by the Poly(ADP-Ribose)Polymerase Inhibitor PJ34 After Stroke and Thrombolysis in Mice. Mol Neurobiol 55, 9156–9168 (2018). https://doi.org/10.1007/s12035-018-1063-3

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